Management of acute seizure and status epilepticus. Apisit Boongird, MD Division of Neurology Ramathibodi hospital

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1 Management of acute seizure and status epilepticus Apisit Boongird, MD Division of Neurology Ramathibodi hospital

2 Outlines Seizure cluster/ Acute repetitive seizures Status epilepticus

3 Seizure cluster

4 A 45-yo male with past medical history of brain tumor s/p partial tumor removal presented to the outpatient clinic with chief complaint of frequent and repetitive focal seizures with preserved awareness for a day. Each seizure was characterized by left face clonic with preserved awareness, lasting for two hours. He had experienced seizure clusters, 4 times a day. He had one GTCs.

5 Definition of epileptic seizure by the International League Against Epilepsy (ILAE) An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsia, 46(4): , 2005

6 Acute Repetitive Seizures (ARS) The practical definition of acute repetitive seizures has not been established. Acute repetitive seizures is neurologic emergency and a common clinical phenomenon describing an increase in seizures occurring over a specific period of time (ranging from several minutes up to 24 hours). Acute repetitive seizures may include any type of seizure and may vary in severity, but by definition there is complete recovery in between seizures. Curr Opin Neurol 2015;28(2):143Y150.

7 Oral tablet benzodiazepine Lorazepam Clonazepam Clobazam

8 Outpatient acute benzodiazepine therapy Rectal diazepam is the only currently marketed treatment available for use by nonmedical caregivers in the USA, and buccal midazolam is approved in the European Union.

9 Outpatient acute benzodiazepine therapy Medications Formulation Notes Diazepam Midazolam Lorazepam Progesterone oral tablet rectal gel (FDA approved) intramuscular buccal intranasal intramuscular oral tablet intranasal sublingual cyclic natural progesterone N Engl J Med 1998; 338: and Neurology 1998; 51: The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) in pre-hospital status epilepticus catamenial epilepsy Neurology 2014; 83: CNS Drugs (2015) 29:55 70

10 Management of acute repetitive seizures (ARS) Diagnosis of seizure clusters Identify the etiology of ARS Benzodiazepines remain the mainstay of therapy in ARS. The treatment of ARS includes the usage of extra doses of usual antiepileptic medications and oral benzodiazepines (diazepam or lorazepam) for mild ARS. Educating the patient and families about seizure first aid and the use of rescued anti-seizure medications.

11 Status epilepticus (SE)

12 Status epilepticus Status epilepticus(se) is a neurologic emergency with high morbidity and mortality. It represents the persistence of abnormal excitation and the ineffective recruitment of inhibition. The management of SE requires immediate action and diligence to avoid pharmacoresistance and brain injury.

13 Old definition of SE A definition of more than 30 minutes of continuous seizure activity or two or more sequential seizures without full recovery of consciousness between was widely adopted, citing neuronal damage in animal models beyond this timeframe. Epilepsy Foundation, 1993

14 Lothman 1990

15 Phase 1: compensation Cerebral changes increased cerebral blood flow increased cerebral metabolism increased lactate concentration increased glucose concentration Systemic and metabolic changes hyperglycemia lactic acidosis Autonomic and cardiovascular changes increased blood pressure increased cardiac output massive catecholamine release cardiac dysthymia urine incontinence J Neurol Neurosurg Psychiatry 2001;70(suppl II):ii22 ii27

16 Phase 2: decompensation Cerebral changes failure of cerebral autoregulation hypoxia hypoglycemia increased intracranial pressure and cerebral oedema Systemic and metabolic changes hypoglycemia hypokalemia/ hyperkalemia metabolic and respiratory acidosis hepatic and renal dysfunction consumptive coagulopathy DIC rhabdomyolysis, myoglobinuria Autonomic and cardiovascular changes hypoxia falling blood pressure falling cardiac output cardiac failure respiratory failure hyperpyrexia J Neurol Neurosurg Psychiatry 2001;70(suppl II):ii22 ii27

17 Epilepsia, 56(10): , 2015

18 Type of SE Operational dimension 1 Time (t1), when a seizure is likely to be prolonged leading to continuous seizure activity Operational dimension 2 Time (t2), when a seizure may cause long term consequences (including neuronal injury, neuronal death, alteration of neuronal networks and functional deficits) Tonic- clonic SE 5 min 30 min Focal SE with impaired consciousness Absence status epilepticus 10 min > 60 min min a unknown a= Evidence for the time frame is currently limited and future data may lead to modifications Epilepsia, 56(10): , 2015

19 Classification of SE 1 Semiology 2 Etiology 3 EEG correlates 4 Age Epilepsia, 56(10): , 2015

20 Axis 1: Semiology The presence or absence of prominent motor symptoms The degree (qualitative or quantitative) of impaired consciousness Epilepsia, 56(10): , 2015

21 Axis 1: Semiology A) With prominent motor symptoms A.1 Convulsive SE (CSE, synonym: tonic clonic SE) A.1.a. Generalized convulsive A.1.b. Focal onset evolving into bilateral convulsive SE A.1.c. Unknown whether focal or generalized A.2 Myoclonic SE (prominent epileptic myoclonic jerks) A.2.a. With coma A.2.b. Without coma A.3 Focal motor A.3.a. Repeated focal motor seizures (Jacksonian) A.3.b. Epilepsia partialis continua (EPC) A.3.c. Adversive status A.3.d. Oculoclonic status A.3.e. Ictal paresis (i.e., focal inhibitory SE) A.4 Tonic status A.5 Hyperkinetic SE Epilepsia, 56(10): , 2015

22 Axis 1: Semiology (B) Without prominent motor symptoms (i.e., non- convulsive SE, NCSE) B.1 NCSE with coma (including so-called subtle SE) B.2 NCSE without coma B.2.a. Generalized B.2.a.a Typical absence status B.2.a.b Atypical absence status B.2.a.c Myoclonic absence status B.2.b. Focal B.2.b.a Without impairment of consciousness (aura continua, with autonomic, sensory,visual, olfactory, gustatory, emotional/ psychic/experiential, or auditory symptoms) B.2.b.b Aphasic status B.2.b.c With impaired consciousness B.2.c Unknown whether focal or generalized B.2.c.a Autonomic SE Epilepsia, 56(10): , 2015

23 Axis 2: Etiology Known (i.e., symptomatic) - Acute (e.g., stroke, intoxication, malaria, encephalitis, etc.) - Remote (e.g., posttraumatic, postencephalitic, poststroke, etc.) - Progressive (e.g., brain tumor, Lafora s disease and other PMEs, dementias) - SE in defined electroclinical syndromes Unknown (i.e., cryptogenic) Epilepsia, 56(10): , 2015

24 Axis 3: Electroencephalographic correlates Currently there are no evidence-based EEG criteria for SE. Epilepsia, 56(10): , 2015

25 EEG patterns in SE 1. Location: generalized (including bilateral synchronous patterns), lateralized, bilateral independent, multifocal. 2. Name of the pattern: Periodic discharges, rhythmic delta activity or spike-andwave/sharp- and-wave plus subtypes. 3. Morphology: sharpness, number of phases (e.g., triphasic morphology), absolute and relative amplitude, polarity. 4. Time-related features: prevalence, frequency, duration, daily pattern duration and index, onset (sudden vs. gradual), and dynamics (evolving, fluctuating, or static). 5. Modulation: stimulus-induced vs. spontaneous. 6 Effect of intervention (medication) on EEG. Epilepsia, 56(10): , 2015

26 Axis 4: Age 1. Neonatal (0 to 30 days) 2. Infancy (1 month to 2 years) 3. Childhood (> 2 to 12 years) 4. Adolescence and adulthood (> 12 to 59 years) 5. Elderly ( 60 years) Epilepsia, 56(10): , 2015

27 Management of status epilepticus

28 Principle of management in patients with SE 1. Stop both ongoing clinical and electrographic seizures 2. Identify and treat the etiology of SE 3. Identify and treat the complications of SE

29 Choosing the anti-seizure medications Age Clinical seizure type: - CSE and NCSE Comorbidities - cardiovascular disease - liver disease - kidney disease Anti-seizure medications - administration - mechanism of action - pharmacodynamics - pharmacokinetics - efficacy for seizure type - recommended doses - adverse effects - drug interactions History of drug allergy - minor rash to SJSs

30 Convulsive status epilepticus (CSE)

31 Definition of CSE CSE is a convulsive seizure lasting more than 5 min or consecutive seizures without recovery of consciousness. In the case of convulsive SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. Epilepsia, 56(10): , 2015

32 Type of SE Operational dimension 1 Time (t1), when a seizure is likely to be prolonged leading to continuous seizure activity Operational dimension 2 Time (t2), when a seizure may cause long term consequences (including neuronal injury, neuronal death, alteration of neuronal networks and functional deficits) Tonic- clonic SE 5 min 30 min Focal SE with impaired consciousness Absence status epilepticus 10 min > 60 min min a unknown a= Evidence for the time frame is currently limited and future data may lead to modifications Epilepsia, 56(10): , 2015

33 Ann N Y Acad Sci 2016;1378: Time is the brain! The response to AEDs treatment is decreasing with time and ongoing seizures probably due to the following reasons; - Functional GABA receptors are decreased due to internalization of GABA receptors. - NMDA receptors are up-regulated. This can resulted in calcium influx intracellularly which makes seizure control more difficult and may causes cellular damage and secondary brain injury. - There is the upregulation of drug-efflux transporters such as P- glycoprotein. - Ongoing status can resulted in an increment of pro-inflammatory agents. Epilepsia 2009;50(Suppl. 8):19 21.

34 The US Department of Veterans Affairs (VA) Cooperative Study randomized controlled clinical trial Five-year randomized, double blind, multicenter trial of four intravenous regimens 518 pts with GCSE Classified into 1. Overt SE (n=384 pts) 2. Subtle SE (n= 134 pts) 1.Lorazepam 2.Phenobarbital 3.Phenytoin 4. Diazepam followed by Phenytoin Conclusions As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam and phenytoin, it is easier to use. N Engl J Med 1998;339(12):792Y798

35 Established Status Epilepticus Treatment Trial (ESETT) Full title: A Multicenter, Randomized, Blinded, Comparative Effectiveness Study of Fosphenytoin, Valproic Acid, or Levetiracetam in the Emergency Department Treatment of Patients With Benzodiazepine-refractory Status Epilepticus Estimated study completion date: in July 2020

36 Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp

37 Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp

38 Treatment phases of CSE Stage 1 (early or impending CSE) - Benzodiazepines are the drugs of choice. - RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial) IV lorazepam vs IM midazolam* - AES guideline state that IM midazolam has a superior effectiveness compared to intravenous lorazepam in adults with CSE without established intravenous access (Level A)** *N Engl J Med 2012; 366: **Epilepsy Curr 2016;16:48 61.

39 Treatment phases of CSE Stage 2 (Established SE): CSE persisting after first-line treatments - phenytoin (fosphenytoin) - phenobarbital - valproic acid - levetiracetam - lacosamide

40 Treatment phases of CSE Stage 3 (refractory CSE): CSE persisting > 60 minutes after second-line treatments - Anesthetic agents are the drugs of choice for the treatment of refractory CSE.

41 Midazolam Midazolam Loading dose Initial rate Maintenance dose 0.2 mg/kg IV over 2 to 5 minutes; 0.1mg/kg/hr 0.05 to 2.9 mg/kg/hour repeat 0.2 to 0.4 mg/kg boluses every 5 minutes until seizures stop, up to a maximum loading dose of 2 mg/kg Mechanism of action of midazolam Onset of action Half-life elimination Metabolism Excretion Dosing: hepatic impairment Dosing: renal impairment Adverse effects GABA-A agonists 3-5 minutes 3 hours hepatic CYP3A4 urine no data; use with caution no data; use with caution respiratory and cardiovascular depression development of tachyphylaxis with prolonged infusions

42 Propofol Propofol Loading dose Initial rate Maintenance dose 1 to 2 mg/kg IV over 3 to 5 minutes; 20 microgram/kg/min; 30 to 200 microgram/kg/min titrated repeat boluses every 3 to 5 minutes bolus and increase rate to EEG with 5 to 10 until seizures stop, up to maximum total until seizure control microgram/kg/min every 5 minutes or loading dose of 10mg/kg 1 mg/kg bolus for breakthrough status epilepticus Mechanism of action of propofol Onset of action Half-life elimination Metabolism Excretion Dosing: hepatic impairment Dosing: renal impairment Adverse effects GABA-A agonists, N-methyl-D-aspartate (NMDA) antagonist 30 seconds 40 minutes- 7 hours hepatic urine no dosage adjustment necessary no dosage adjustment necessary respiratory and cardiovascular depression, propofol infusion syndrome, which includes potentially fatal myocardial failure with lactic acidosis, hypertriglyceridemia, and rhabdomyolysis

43 Thiopental Thiopental Loading dose mg IV drip > 20 seconds then 50 mg IV every 2-3minutes until seizure was stopped. Maintenance dose 3-5 mg/kg/hour Mechanism of action of thiopental Onset of action Half-life elimination Metabolism Excretion Dosing: hepatic impairment Dosing: renal impairment Adverse effects GABA-A agonists 30 seconds 5-22 hours hepatic, primary to inactive metabolites urine, primary to inactive metabolites no data no data dose-dependent respiratory and cardiovascular depression, long recovery time, immunosuppression

44 Ketamine Ketamine Loading dose Initial rate Maintenance dose 1 to 4.5 mg/kg with 1.5 mg/kg every 3 5 to 125 microgram/kg/min supplements of mg/kg to 5 minutes until ( mg/kg/hr) every minutes or 10 to seizures stops, up 50 microgram/kg/min to a maximum of 4.5 mg/kg Mechanism of action of ketamine Onset of action Half-life elimination Metabolism Excretion Dosing: hepatic impairment Dosing: renal impairment Adverse effects N-methyl D-aspartate (NMDA) receptor antagonists 30 seconds 2.5 hours hepatic via CYP3A4 urine no data no data elevation of blood pressure, increased intracranial pressure

45 Topiramate Loading dose Maintenance dose Side effects Topiramate 100 mg PO q 12 hours mg/day q 12 hours metabolic acidosis topiramate+propofol refractory acidosis topiramate+ sodium valproate hyperammonemia Mechanism of action of topiramate Blockade of the ionotropic glutamatergic AMPA/kainate receptors Blocks neuronal voltage-dependent sodium channels Enhancement of GABAergic activity 2-4 hours 20 hours Minor amounts metabolized in liver Onset of action Half-life elimination Metabolism Excretion Urine 70% Dosing: hepatic no data; use with caution in patient with impairment severe hepatic impairment Dosing: renal impairment reduce dose to 50% if CrCl < 70 Adverse effects drowsiness, metabolic acidosis, hyperammonemia

46 Refractory status epilepticus (RSE) Quick check lists - The patient must be intubated and should be admitted in the intensive care unit for respiratory monitoring, and hemodynamic monitoring. - Continuous electroencephalography(ceeg) monitoring is critical during the treatment of RSE and should be performed in every patient with RSE (if possible).

47 ceeg monitoring

48 The usefulness of ceeg monitoring ceeg monitoring is necessary to confirm that ongoing seizures have been completely stopped and under controlled after the treatment of RSE. Ongoing electrographic seizures may be masked when using paralytics for intubation; therefore patients may continue to seize without any clinical manifestations. The depth of anesthesia, the level of CNS suppression, degree of encephalopathy, ongoing electrographic seizures can be assessed by using the ceeg monitoring. Thus, the information from ceeg monitoring is very useful for the treatment of RSE including the adjustment of anti-seizure medications.

49 Optimal electroclinical endpoint of treatment To best of our knowledge, the optimal electroclinical endpoint of treatment has not been studied in a well-designed clinical trials. Therefore, it is uncertain whether the goal should be simple cessation of both clinical and electrographic seizures, or some degree of suppression of cerebral activity. Thai clinical practice guideline: no clinical and electrographic seizures plus burst suppression with interburst interval of 5-15 seconds for 24 hours.

50 Burst suppression with interburst intervals of 3 seconds 1 sec BURST SUPPRESSION BURST

51 Burst suppression with interburst intervals of 5 seconds BURST SUPPRESSION

52 Tapering off anesthetic agents in patient with RSE Thai clinical practice guideline: no clinical and electrographic seizures for hours. Before tapering off anesthetic agent, it is critical that high therapeutic levels of at least one longer-acting anti-seizure medication be maintained before tapering continuous infusions. - avoid anti-seizure medications with a primarily GABAergic mechanism - avoid > 2 anti-seizure medications - try anti-seizure medications with multiple mechanisms of action and low drug interactions

53 Tapering off anesthetic agents in patient with RSE When electrographic seizures re-appear during tapering off anesthetic agent, most experts recommend to re-treat with higher doses of the anesthetic agent, or for longer at doses that were successful earlier. Additional anti-seizure medications should be immediately prescribed before considering the next attempt.

54 Treatment phases of CSE Stage 4 (super-refractory CSE)*: CSE persisting for more than 24 hours after administration of third-line treatments - anesthetic agents - ketamine - immunomodulatory therapy - hypothermia - new anti-seizure medications - ketogenic diet* *Brain 2011;134: **Neurology Mar 7;88(10):

55 Perampanel (PER) PER has a novel mechanism of action. It is a first in class orally active, selective, non-competitive alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor agonist. PER - initial dose in case small case series: 2-32 mg - adult patients with refractory and super-refractory status epilepticus in a neurological intensive care unit Epilepsy Behav Aug;49:354-8.

56 Perampanel Fycompa tab 2 mg (film-coated) Fycompa tab 4 mg (film-coated) Fycompa tab 8 mg (film-coated)

57 Focal motor status epilepticus

58 Epilepsia partialis continua (EPC) Treatment - identify and treat causal or precipitating factors - anti-seizure medications - first-generation: carbamazepine, valproate, clonazepam - second-generation: topiramate, levetiracetam

59 Non-convulsive status

60 Non-convulsive status epilepticus (NCSE) Positive symptoms - agitation, aggression, delirium, psychosis - facial twitching, automatisms - sustained eye deviation, nystagmus Negative symptoms - aphasia - mutism - eye staring - confusion, lethargy, coma

61 Non-convulsive status epilepticus (NCSE) Patients with NCSE may have no clinical signs or develop only subtle jerks of the face, eyes, and extremities. NCSE is diagnosed only by electroencephalography(eeg).

62 Salzburg EEG consensus criteria for non-convulsive status epilepticus (SCNC) Patients without known epileptic encephalopathy EDs > 2.5 Hz, or EDs 2.5 Hz or rhythmic delta/theta activity (> 0.5Hz) AND one of the following: - EEG and clinical improvement after IV AED*, or - Subtle clinical ictal phenomena, or - Typical spatiotemporal evolution** Patients with known epileptic encephalopathy Increase in prominence or frequency when compared to baseline with observable change in clinical state Improvement of clinical and EEG* features with IV AEDs * If EEG improvement without clinical improvement, or if fluctuation without definite evolution, this should be considered possible NCSE. ** Increment onset(increase in voltage and change in frequency), or evolution in pattern(change in frequency > 1Hz or change in location), or decrementing termination(voltage and frequency). EDs: epileptiform discharges(spikes, polyspikes, sharp-waves, sharp-and-wave complexes) IV AED: intravenous antiepileptic drugs Epilepsy Behav: E&B 2015;49(August) Lancet Neurol 2016;15(September (10))

63 Management of NCSE The aggressiveness of anti-seizure medication treatment should be individualized on each patient with NCSE. The following variables should be considered; - degree of impairment of consciousness - etiology

64 NCSE without coma For NCSE patients without coma, we suggest treatment with an IV benzodiazepine combined with an IV noncomainducing anti-seizure medications(aeds). Noncoma-inducing AEDs - phenytoin - sodium valproate - levetiracetam - lacosamide

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80 NCSE with coma In the critically ill coma population, there is considerable controversy about whether to treat NCSE as aggressively as convulsive status epilepticus.

81 Refractory nonconvulsive status epilepticus Refractory status epilepticus (RSE) refers to status epilepticus that continues despite administration of therapeutic doses of two or more anti-seizure drugs. Treatment of refractory NCSE must be individualized. Examples of situations that may warrant aggressive therapy include subtle status epilepticus developing from generalized convulsive seizures, NCSE with acute brain injury, an cryptogenic new-onset refractory status epilepticus (NORSE).

82 NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. Epilepsia. 2018;59:

83 NCSE with coma

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87 American Clinical Neurophysiology Society s Standardized Critical Care EEG Terminology: 2012 version J Clin Neurophysiol 2013;30: 1 27)

88 Postanoxic status epilepticus (PSE) Thai epilepsy society ( issue-1-jan-april/)

89 The end